Method for decreasing the reproductive function of mammals

ABSTRACT

A METHOD O FOR ALTERING THE REPRODUCTIVE FUNCTION OF MAMMALS BY ADMINISTERING A PHARMACOLOGICALLY EFFECTIVE AMOUNT OF CERTAIN ORGANOSILICON COMPOUNDS. AS A MEANS OF ILLUSTRATION, ONE CAN ORALLY OR PARENTERALLY ADMINISTER FROM 1.0 MG. TO 5000 MG. PER KILOGRAM OF BODY WEIGHT (EITHER AS A SINGLE DOSE OR AS A DAILY DOSAGE OVER A PERIOD OF TIME) OF AN ORGANOSILICON COMPOUND OF THE FORMULA   2,2,4,6,8,8-HEXA(H3C-),4,6-DIPHENYL-CYCLOTETRASILOXANE   THREBY RENDERING THE SUBJECT (EITHER A MALE OF FEMALE MAMMAL) INFERTILE.

United States Patent Us. or. 424-184 2 Claims ABSTRACT OF THE DISCLOSUREA method for altering the reproductive function of mammals byadministering a pharmacologically effective amount of certainorganosilicon compounds. As a means of illustration, one can orally orparenterally administer from 1.0 mg. to 5000 mg. per kilogram of bodyweight (either as a single dose or as a daily dosage over a period oftime) of organosilicon compound of the formula CHz-di--O-dl-CH;

11H: CtHs thereby rendering the subject (either a male or female mammal)infertile.

' This application is a continuation-in-part of US. application, Ser.No. 741,336, filed July 1, 1968, now abandoned.

.This invention relates to a method for altering the reproductivefunction of mammals. We have discovered that the administration of apharmacologically effective amount of certain organosilicon compoundscanalter the reproductive function of mammals: More precisely, a malemammal so treated exhibits androgen depressant effects. For example, thesex accessory organs of the male (seminal vesicle, prostate) canbenreduced in function and/ or size and with sufficient dosage, the malecan also b'e'rendered infertile as a result of depression of testes sizeand function. A female mammal so treated exhibits an alteration offertility, i.e., the female mammals capability to conceive is inhibitedsuch that the female may berendered infertile or abort if pregnant.

The principal object of this invention is to provide therapeuticallyeffective organosilicon compounds which can render a male or femalemammal infertile. Another principal object of this invention is toprovide a method of administering: certain organosilicon compounds whichcan be -usefuliin the treatment of prostatic hypertrophy by depressingandrogen function in males. It still another obiect of this invention toprovide a method of administeringv certain organosilicon compounds tofemales whereby the females capability to conceive or support and carrya living fetus'through a normal pregnancy to a healthy birthcan beinhibited. These and other attendant objects will become morereadily-apparent from the detailed description which follows. Thisinvention relates to a method for altering the reproductive function ofmammals which comprises adminis tering from 1.0 mg. to 5000 mg./kg. ofcertain organo- SlllCOD. compounds to a mammal, said certainorganosilicon compounds being selected from the group consisting of (11)Siloxanes having three silicon atoms per molecule said silicon atomsbeing linked by divalent oxygen atoms, at least one of the silicon atomshaving one valence being satisfied by a substituent selected from thegroup consisting of a phenyl radical and a hydrogen atom, the remainingvalences of the silicon atoms being satisfied by substituents selectedfrom the group consisting of phenyl radicals, hydrogen atoms, alkylradicals having from 1 to 6 carbon atoms inclusive, and hydroxylradicals, there being no more than two hydroxyl radicals orsilicon-bonded hydrogen atomsper molecule and therev being no more thanfour phenyl radicals per molecule, and I (12) An equilibrated copolymermixture consisting primarily of about 60 weight percent ofphenylm'ethylsiloxane units and about 40 weight percent ofdirnethylsiloxane units, said copolymer mixture being characterized byhaving a viscosity of 18.6 cs. to 21.7 cs. at 25 C., a specific gravityof 1.061 to 1.069 at 25 C., a refractive index of 1.4871 to 1.4929 at 25C., an open cup flash point of 275 F. to 370 F., and an acid No. oftrace to 0.0028 mg. of KOH per g. of sample.

Illustrative of the siloxanes (11) which are operable i The certainorganosilicon compounds noted herein can be readily prepared by wellknown techniques described in the literature, e.g., by the cohydrolysisof chlorosilanesor by a suitable Grignard reaction.

The process of the present invention is operative on any mammal, e.g.,rodents such as mice, rabbits and rats; domestic animals such as cats,swine, dogs, cattle, horses, and sheep; animals Wild in nature such asdeer, fox, wolves and lynx; and primates such as monkeys and man.

One can administer the certain organosilicon compounds in anypharmacologically acceptable manner. They can be orally administered,parenterally administered or, in certain species, topicallyadministered. The parenteral mode of administration would, of course,in-

clude subcutaneous administration, intramuscular admin istration and thelike.

It is of importance to note that the organosilicon compounds describedherein can be administered either in pure form in or combination with apharmaceutically acceptable carrier or diluent. Suitable carriersinclude'sesame oil, corn oil, mineral oil and other well known fatsoluble carriers commonly employed in numerouspharmaceuticalpreparations.

As mentioned herein, the dose range of the organ0- silicon compound isin a pharmacologically eifective amount. A dose range of from about 1.0mg. to, about 5000 mg. per kilogram of body weight has been found to besuitable; however, the precise dosage is ultimately dependent upon theparticular compound and its iso-" mers, the mammal used, the vehicleused, the route of administration, and the specific effects one wishesto achieve. The organosilicon compound may be administered as a singledose or it may be administered in daily dosage over varying periods oftime, e.g., from about 7 to about 30 days or more.

The time required to achieve the desired effect is also variable,ranging anywhere from days to weeks or months, depending upon variousfactors, e.g., the species of mammal, dosage, route of administration,and the desired effect one wishes to achieve.

The particular alteration of androgen functions which have been observedafter administering the compounds of the present invention to malemammals are a decrease in sex accessory organ function (decreasedseminal fluid) and size (decreased seminal vesicle) and a decrease inprostatic or testicular function (decreased sperm count or size.

In view of the above, the method of this invention can be useful fordecreasing the size of male sex accessory organs. In this regard, sexaccessory organs are more sensitive than the testes to these certainorganosilicon compounds so that it is possible to decrease prostaticfunction and size without producing a significant effect on testicularsize.

Furthermore, the method of this invention can be particularly useful forthe treatment of prostatic hypertrophy. For example, by orallyadministering a-compound of the formula g at a daily (seven daily doses)dosage level of mg. per kg. of body weight, it has been found that theprostate is significantly reduced in size.

If a high dosage level is maintained over a fairly long period of timein females prior to, during and/or following copulation, the anticipatedembryo may fail .to form or it may be resorbed by the female mammal. i v

It is also possible to prevent pregnancy (contraception) or abortpregnancy in female mammals because of an estrogenic activity ofcertain'of theorganosiliconcompounds described herein. I

In all of the asti a e e he ineeq esiselaq: TABLE P tiofis'are'freveisiblef lwmmm I tag; The following egramples are illustrativeonly and should M i v w ga y not be construedhs hmi' the invention whichis propi ggfig gfi "igg i' W r r S8 61'0 g erly delineated in theappended claims. daily fir t "j: 7 Compounds i kg. doses dose SpeciesEXAMPLE 1 on. on v 100 1 5 Rat.

on-si-o-srn Q This example illustrates androgen-depressant activity I vof a certain organosilicon compound in the male rat. CH! M A. group ofmale rats (Sprague-Dawley strain) were 7 8 f orally dosed via gastricintubation with an organosilicon (0H,);Si-O-sr-0-sr011 compound of theformula v H,

00115 100 7 -8 IvRat;

/SiCHs ,(l) v o v onorsi-d-sr-(cnm g$ 0 g g; (14H; 0 00H: (CH1)? i0.l C|(Edit 100 7 v 8 Eat.

(CH;)zSi-0Si-CH| l l I I (CH3)2S1OS(CH3)2 c n c H R Thewammalsiwere,admmistered. 100 mg./kg. of body 5 7 8 at weight of the compound for aperiod of seven days with cmSi-(PSPCH' autopsy on day eight. Final bodyweights were determined in-t the tasted state just prior to sacrifice.Table I Hr illustratesthe-androgen-depressant activity noted above. sHro a I I 'TABLEI {Androgen-depressant activity of a certain organosilieoncompound in the male rat] w Mean Mean Mean Mean initial final seminalseminal Mean Mean body body fluid vesicle prostate testes weight weightratio, ratio, ratio, ratio, Group 1: (grams) (grams) iS.E.; =l=S.E.;=!=S.E.; =l=S.E.; ---&. 0 5] 4 88333 333? 3835? 3835? (Gnome-Hm" I si-oa-si I .00115 .00100 .00017 .00860 W 3. ncome 5:.00005 1.00006=l=.00018 .-S i0 SiE3sfi|.n w din) cm 1 Ratio equals organ or fluid{might (grams)lfinal body weight (grams).

i p .D01 compared to contr Daily oral dosing of mgJkg. of body weightfor 7 days with autopsy on day 8.

EXAMPLE 2 This example illustrates the structure-activity-relation shipbetween'rat androgen-depressant activity and certain orgariosiliconcompounds;

wanna [A. Group of compounds with oral dose 01 100 mgJkg. oi body weightfor efiect] Sacri-r J fice day fol- I Daily Namlow-v dose bar of 1 ing 1we mg./ daily -first Compounds kg. doses dose Species 05H: A 100 7 8Rat. CH=-?i-OH can; i I...

06B! 100 7 8 Rat.

(CHshSi-O-SKCHQ:

1H: r l CH; OH; 100 6 Rat.

cgeaao snotsi mh 0H5 Hi i I i A group of male rats and mice(Sprag-ue-Dawley strain) were orally dosed with the organosilic oncompounds heretofore defined which were diluted in sesame oil. Oraladministration was achieved via gastric intubation. The period of dosageranged from one to seven days 'at dose level'sof 1;10, 33,50,100,1670,"and 5000"'mg./ kg. of body weight. Final body weights weredetermined in the fasted state just prior to sacrifice. Sacrifice wascarried out on day fouiQ-five, six, seven or eight depending upontheparticular dosageregimen. Various organ weights were determined andratios of the organ weights (grams) to final body weight (grains) weredetermined for comparison in both control and treated animals.

TabledI (A through 1)) indicates the structure-activityrelationshipreferred to above with respect to dosage range for effect. fir

These" dosages represent threshold doses for'depression of seminalfluid, seminal vesicle, and/or testes weight ratios. 1

" aim 11a Sacrifiee Numday her: fellow- Daily ing dose, daily first ICompounds mg.l,g. doses dose Species H; 500 5 6 Rat. CHE-Sb-Cl 01H; 5003 4 Mouse. CeH --?lO-Sl(CH:):

CHI

00H! 500 3 4 D0.- (CH:):Si0?i0-Si(CH;)

Cells 500 3 4 Do (CHaliSi-O-Sl-O-SKCH h Vehicle, it any, sesame oil.

TABLE I t [0. Group of compounds with oral dose of 1,000 mgJkg. oi bodyweigh ior efiect] Sacri- Daily Numfice day dose, ber of followmg./ dailying first Compounds kg. doses dose Species CH1 1, 000 1 5 Rat.

CH -Sl-COH (30H; 1,000 1 5 Rat.

(CHQ Si-O-Si-O-SKCHQ;

SK-(CHQ: 1,000 1 5 Bat; CHzSl Sl(CH1)s CaHl C0115 00H; 1, 000 1 5 Rat.

CH;-Sl-O-Si-CH:

l l (CHa):S i-0-S 1(CH3):

Vehicle, it any, sesame oil.

TABLE IID ID. Group of compounds with oral dosage range of 1,670 to5,000 mgJkg. of body weight for effect] Sacriflee Numday her follow-Daily of ing dose, daily first Compounds mgJkg. doses dose Species CH1.670 3 4 Mouse.

' cringei-o-si-o -suomn CH; 1,670 3 4 Do. (CH|)aSi-O-?t-0-Si(CH|)a 00HCeHs 1, 670 5 6 But; no SiOS 10H CH; H;

Compounds mg./,g. doses dose Species CH=CH1 1,670 3 4 Mouse.

CH;Si0'--Si(CHa)| CeHs 0H5 5,0oo 5 6 1m CH Si-O-Si(CHl)t I I I CnHs5,000 5 6 Rat.

CH:-Si-OSi(CH,);

( JoHs C6H5 5,000 5 6 Rat. onoisi-o-si-o-sncn'm CeHs 5,000 5 6 Rat.

(CHa);Si0Si0-Si(CH;)

Vehicle, ii any, sesame oil.

EXAMPLE 3 TABLE IIIA [Androgendepressant activity of a certainorganosillco'ncompound in the male rat] Mean seminal vesicle ratio=i=S.E.;' as percent of control 1 (a) Control (sesame oil) lhHr 00 s I Si-O-S 1-4711;

CHI C CH;S lOlSi Group(2,4-cia-dlphenyl-2,4,6,6,8,8-heramethyloyclotetrasiloxane) eHs (IJH:l-OSl- -CHs CH1 CH 0 CHrSlO-?l CH: CsHl (2,B-tram-dlphenyl-2,4,4,6,8S-hexamethyleyclotetrasiloxanei (feHs' 'GH:

CH:Sl 0 S1 H: CH:

(d) (2,6-cis-diph enyl-2,4,4,6,8,8-hexamethylcyclotetrasiloxane)(2,6-cis-dipheny1-2,4,4,6,8,8-hexamethylcyclotetrasiloxane) 1 Compoundadministered in sesame oil orally daily 7 days with autopsy on day 8.Ten animals per group.

1 Ratio equals organ weight/final body weight.

3 p .001 compared to control.

at dose listed for TABLE IIIB t e male mouse Mean e prostate Dose)weight Group mg.lkg. ratio (a) Control (sesame oil) .00130 (b) C H 33300112 100 w 00160 T l 0 CH: 0 CH3 I (CH3); S i 0 i CeHs 2,4-tram-diphenyl, 2, 4, 6, 6-tetramethylcyclotrisiloxane).

(c) 041B: 333 00088 100 00090 T 0 CH3 0 (65H; (0119281 O ?i (2,Mis-diphenyl-Z, 4, 6, G-tetramethyleyclotrisiloxane).

1 Compound administered in sesame oil orally daily at dose listed forseven days with autopsy on day 8.

3 Ratio equals organ weight/final body weight. 8 p .001 compared tocontrol.

EXAMPLE 4 This example illustrates the estrogen-like activity of acertain organosilicon compound in the immature female rat. 1

An immature female Wistar rat was orally administered (via gastricintubation) either mg./kg. of body weight or 200 mg./kg. of body weightof an organosilicon compound of the formula for three days with autopsyon day four. The percent increase in uterine weight was determinedbetween the control (sesame oil) and the treated animals. Table IVillustrates estrogen-like activity in the immature female rat based uponpercent increase in uterine weight.

Daily oral dosing for 3 days with autopsy on day 4. "p .01 compared tocontrol.

EXAMPLE 5 certain organosilicon compound in the immature female rat.

Or ganosilicon compound induced depression of uterine weight stimulatedby estrodial benzoate was usedas a measure of anti-estrogen activity.Table V illustrates the results obtained.

TABLE V [Anti-estrogen activity of a certain organosilicon compound inthe immature female rat] Mean uterine weight Organo- (grams)! silicongrams dose, final body Group mgJkg. 11 weight (A) Control (sesame oil) 661. 64

(B) Estradial benzoate (1.0 mg.

total dose)- 6 197. 06

(C)-.'." (CH3)? (CH2)2" 5. 0 6 194. 7:

(Sgi-O- S i l l ?iOSi-C0H a): H:

(D) (CHa)2SiO-Si(CHs)a* 20.0 6 169.33

Compound administered orally for three days with autopsy on day 4.Estradial benzoategiven subcutaneouslyingroupsB, C andD.

EXAMPLE 6 This example illustrates the antifertility activity of acertain organosilicon compound administered orally for seven days priorto mating to proven breeder female mice. A group of untreated femalemice (Cox strain) were mated with a group of untreated male mice andanimals which became pregnant and delivered an average normal litter inthis first mating were then selected as proven breeders for a secondmating. These mice in the second mating were orally dosed (via gastricintubation) with either nothing, sesame oil, or two different doses (50mg./ kg. of body weight or 200 nag/kg. of body weight) of anorganosilicon compound of the formula i (cnofm-o-sr-wng,

Table VI illustrates the antifertility; activityi noted above. I V

TABLE VI [limiter-tint activity of a certain organosiiicon compoundadministerecll orally for seven days prior to mating to'proven breederfemale mice Second mating First mating I Number Mean Number Meanpregnant number pregnant] number tota pups/ tot pups] number femalenumber female (A) Control (no treatment) 3/3 9. 33 3/3 13.

(B) Sesame oil 3/3 10. 33 3/3 12. (g) (C) (CHJh-Si-O-SKCHa): 3/3 10.331/3 14.

I l (CH:)g- S i-OS i-CcHs (D) (CH|)1--Si-0Si-(CHa)a 3/3 10. 67 1/3 18. 0

EXAMPLE 7 This example illustrates the abortifacient activity of mixedlow molecular weight cyclic methylphenylpolysiloxanes administereddermally from the sixth to the sixteenth day following mating inrabbits.

The mixed low molecular weight cyclic methylphenylpolysilane is acommercially available silicone equilibration product. For purposes ofease, it will be hereafter referred to as Organosilicon Compound A. Itis made by a continuous process technique in commercial, steel equipmentas follows:

To a copolymer mixture B* of phenylmethylsiloxane and dimethylsiloxaneobtained from the sources indicated below, there was added a sufficientamount of a waterwashed, 50 weight percent toluene solution C of ahydrolyzate of phenylmethyldichlorosilane, and a sufficient amount ofdimethylpolysiloxane D in the form of cyclics and hydroxyi-endblockedpolymers having generally from about 3 to 10 siloxane units to yield amixture containing about 6 parts by weight of phenylmethylsiloxane forevery 4 parts by weight of dimethylsiloxane. To this mixture there wasadded sufiicient toluene to make a solution containing about 35 weightpercent of organopolysiloxanes.

This mixture of B, C and D is referred to below as (1). Where it isstated below that a given material is returned to (1), it is meant thatit is placed in the initial reaction chamber as an ingredient for thenext production run of product. correspondingly, the present productionrun received similar ingredients from the production run which precededit, the present material being made in a continuous process.

To (1) there was added a sufficient amount of a 45 weight percentsolution of potassium hydroxide in water to provide about 0.5 mg. ofpotassium for every gram of organopolysiloxane present, and the mixturewas heated with slowly increasing temperature up to the refluxtemperature. The heating was performed under azeotropic conditions.

After about hours of heating at the reflux temperature, the product wasfound' to be an equilibrated phenylmethylsiloxanedimethylsiloxanecopolymer.

The equilibrated mixture was drawn 0E and neutralized to a slightly acidcondition (acid number of about 0.02) by the addition ofdimethyldichlorosilanc. This product was then filtered to remove solidsand stripped at at 8 is composed of dlstillates B1, B2 and B4 andresidue B3 mospheric pressure to about C. The distillate B which wasprimarily toluene, was recycled back to (1) While the residue wasfurther stripped at about 30 mm. of pressure to a pot temperature of 200C. (about 90 C. at the top of the distillation column).

The resulting distillate B was returned to (1) while the residue wasdistilled at a pressure of about 2.5 mm. and a pot temperature of 300 C.(about 180 to C. at the top of the distillation column).

The residue B of this latter distillation was returned as needed to (1).(Occasionally, this residue was discarded if it appeared to contain anexcess of impurities.) The distillate was stripped to about 100 C. at apressure of about 2 mm.

The volatile fraction B of this final distillation was returned to (1)while the residue is the product tested below, known as OrganosiliconCompound A.

Thirty mature doe rabbits (Dutch Belted strain) were divided into threegroups of ten each. One group served as a treated control (distilledwater) whereas the Organosilicon Compound A was administered dermally(test material applied to the shaven back) at dose levels of 50 mg./kg.of body weight and 500 mg./kg. of body weight to the other two testgroups respectively. Ten untreated provcn bucks were used for breedingand each buck was mated to one doe in each of the three groups.Sufiicient females were mated to obtain ten pregnant animals per group.

The abortifacient efiect (number of young dead and alive) is presentedin Table VII.

TABLE VII [Abortil'acient activity of mixed low molecular weight cyclicmethylpheulypolysiloxanes administered dermally from the sixth to thesixteenth day following mating in rabbits] This example illustratesantifertility in the male Macaca mulatta monkey.

A group of male Macaca mulatta monkeys were orally dosed with theOrganosilicon Compound A. of Example 8. Oral administration was achievedvia gastric intubation. Dosage was for 90 days at a level of 50 mg./kg.of body 13 weight or 2000 mg./kg. of body weight daily. After 90 days,an attempt to obtain seminal fluid was made and biopsies were conducted.The results are tabulated in Table VIII.

TABLE VIII [Antitertility activity of mixed low molecular weight cyclicmethylphenylpolysioxanes administered orally for ninety days in the themale Macaca Mulatta monkey] Group n Results Contr01. 3 N o alteration ofseminal ejaculate, testicular size, or spennatogenesis as determined bybiopsy after 90 days of dosing. Organosilicon 2/3 provided seminalejaculate.

Compound A 3 2/3 showed no alteration of testicular size. (50 mgj g 2/3showed no spermatogenic depression. daily dose). Organosilicon 3/3 noseminal ejaculate obtained.

Compound A 3 3/3 animals revealed atrophy of testes. (2,000 mg./kg., 3/3animals revealed spermatogenic depression. daily dose).

That which is claimed is:

1. A method for decreasing the reproductive function of mammalscomprising administering to a mammal an effective amount in the range offrom 1.0 mg. to 10 mg./ kg. of mammal body weight of2,6-cis-diphenylhexamethylcyclotetrasiloxane.

2. The method of claim 1 wherein the decrease in reproductive functionis a reduction in fertility of said mammal.

References Cited UNITED STATES PATENTS 4/1960 May 424-484 5/1968 Grasset al. 424-184

